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We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults.

Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination.

The researchers found that the chemical XAV939 stabilised levels of Axin2 in OPCs in the laboratory. Slices of mouse brain in the laboratory, which had been starved of oxygen or exposed to a demyelinating chemical, showed reduced levels of myelin. Treating these slices of brain with XAV939 reversed this effect.

{Nature Publishing via BioPortfolio} Premyelinating oligodendrocytes are vulnerable to hypoxic injuries, especially during the neonatal period. Here, Fancy et al. find that the Wnt scaffolding molecule Axin2 is crucial for normal remyelination after hypoxic injuries and demonstrate that pharmacological inhibition of tankyrase, which stabilizes Axin2 levels, can promote oligodendrocyte differentiation and recovery after hypoxic and demyelinating injuries.

O2 availability, therefore, may have a direct role in stem cell regulation through HIF‑1α modulation of Wnt/β‑catenin signalling. Activation of the Wnt/β-catenin pathway is characterized by 1) stabilization of cytoplasmic β-catenin after receptor engagement by Wnt ligands; 2) β-catenin nuclear translocation, 3) β-catenin interaction with lymphoid enhancer-binding factor-1/T-cell factor-1 (LEF/TCF) transcription factors; and 4) stimulation of target genes8,9.

To determine whether this pathway is modulated by O2 availability, we transiently transfected murine ES cells and P19 embryonal carcinoma (EC)
cells with a luciferase-based TOP-Flash (TCF optimal promoter) Wnt
reporter plasmid, and compared reporter activity under normoxic (21%
O2) and hypoxic (1.5% O2) conditions. Exposure to hypoxia significantly
enhanced reporter activity (2-fold) in both embryonic cell lines
(Fig. 1a; Supplementary Information, Fig. S1a, b). Hypoxic exposure
also increased levels of nuclear β-catenin, LEF-1 and TCF-1 proteins
(Fig. 1b). Analysis of hypoxic cells by quantitative real-time PCR (qRT–
PCR) showed increased expression (2–6-fold) of Wnt target genes, such
as Axin2 and Dkk‑4 (Dickkopf-4), and β-catenin activators, Lef‑1 and
Tcf‑1 (Fig. 1c). This is consistent with our previous data showing
increased Lef‑1 expression in hypoxic mouse ES cells10. HIF-1α protein
stabilization and upregulation of the HIF-1α target Pgk‑1 confirmed the
induction of a hypoxic response (Fig. 1b, c). Hypoxia exerted a similar effect in stimulated cells.